Abstract | BACKGROUND AND AIMS: APPROACH AND RESULTS: Hepatocyte-specific ATGL knockout (ATGL LKO) mice were challenged with methionine- choline-deficient (MCD) or high-fat high- carbohydrate (HFHC) diet. Serum biochemistry, hepatic lipid content and liver histology were assessed. Mechanistically, hepatic gene and protein expression of lipid metabolism, inflammation, fibrosis, apoptosis, and endoplasmic reticulum (ER) stress markers were investigated. DNA binding activity for peroxisome proliferator-activated receptor ( PPAR) α and PPARδ was measured. After short hairpin RNA-mediated ATGL knockdown, HepG2 cells were treated with lipopolysaccharide (LPS) or oleic acid: palmitic acid 2:1 (OP21) to explore the direct role of ATGL in inflammation in vitro. On MCD and HFHC challenge, ATGL LKO mice showed reduced PPARα and increased PPARδ DNA binding activity when compared with challenged wild-type (WT) mice. Despite histologically and biochemically pronounced hepatic steatosis, dietary-challenged ATGL LKO mice showed lower hepatic inflammation, reflected by the reduced number of Galectin3/MAC-2 and myeloperoxidase-positive cells and low mRNA expression levels of inflammatory markers (such as IL-1β and F4/80) when compared with WT mice. In line with this, protein levels of the ER stress markers protein kinase R-like endoplasmic reticulum kinase and inositol-requiring enzyme 1α were reduced in ATGL LKO mice fed with MCD diet. Accordingly, pretreatment of LPS-treated HepG2 cells with the PPARδ agonist GW0742 suppressed mRNA expression of inflammatory markers. Additionally, ATGL knockdown in HepG2 cells attenuated LPS/OP21-induced expression of proinflammatory cytokines and chemokines such as chemokine (C-X-C motif) ligand 5, chemokine (C-C motif) ligand (Ccl) 2, and Ccl5. CONCLUSIONS: Low hepatic lipolysis and increased PPARδ activity in ATGL/PNPLA2 deficiency may counteract hepatic inflammation and ER stress despite increased steatosis. Therefore, lowering hepatocyte lipolysis through ATGL inhibition represents a promising therapeutic strategy for the treatment of steatohepatitis.
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Authors | Claudia D Fuchs, Richard Radun, Emmanuel D Dixon, Veronika Mlitz, Gerald Timelthaler, Emina Halilbasic, Merima Herac, Johan W Jonker, Onne A H O Ronda, Matteo Tardelli, Guenter Haemmerle, Robert Zimmermann, Hubert Scharnagl, Tatjana Stojakovic, Henkjan J Verkade, Michael Trauner |
Journal | Hepatology (Baltimore, Md.)
(Hepatology)
Vol. 75
Issue 1
Pg. 125-139
(01 2022)
ISSN: 1527-3350 [Electronic] United States |
PMID | 34387896
(Publication Type: Journal Article, Observational Study, Research Support, Non-U.S. Gov't)
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Copyright | © 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. |
Chemical References |
- Fatty Acids, Nonesterified
- Lipase
- PNPLA2 protein, human
- PNPLA2 protein, mouse
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Topics |
- Adult
- Animals
- Diet, Carbohydrate Loading
(adverse effects)
- Diet, High-Fat
(adverse effects)
- Disease Models, Animal
- Fatty Acids, Nonesterified
(metabolism)
- Female
- Hep G2 Cells
- Humans
- Lipase
(genetics, metabolism)
- Lipolysis
(genetics, immunology)
- Liver
(enzymology, immunology, pathology)
- Male
- Mice
- Mice, Knockout
- Middle Aged
- Non-alcoholic Fatty Liver Disease
(etiology, immunology, pathology)
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